Prof C Sale, Dr K Elliott-Sale, Dr M Turner
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
Carnosine (Beta-alanyl-L-histidine) is a histidine containing dipeptide (HCD) first discovered in meat extract by Gulesitsch and Amiradzhibi (1900). Carnosine and its methylated analogues (i.e., anserine and balenine) are abundantly found in the skeletal muscle of many vertebrates, including primates, fish, birds and reptiles (Boldyrev et al., 2013). Other relevant tissues that contain carnosine or other HCDs are the cardiac muscle, olfactory bulb and kidney. Carnosine is formed by the combination of the alpha amino acid L-histidine and the beta amino acid β-alanine; both analogues are synthesised via carnosine methylation (McManus, 1962). β-alanine and L-histidine are easily transported into muscle cells; once these two amino acids are inside muscle cells the carnosine synthase enzyme catalyses their synthesis to carnosine. In muscle cells, β-alanine availability is the rate-limiting step for carnosine synthesis. Despite being a long known compound, the biological and physiological roles of carnosine and other HCDs remain largely unknown.
The pKa of carnosine is ~6.8, which falls well within the mid-point of pH transit range of the skeletal muscle. Therefore, carnosine is believed to act as pH regulator in the skeletal muscle, mostly in type II fibres which are more reliant on anaerobic energy transferring systems and, thus, more prone to marked decreases in intracellular pH. In support of this notion, studies with β-alanine supplementation (capable of increasing muscle carnosine content) have consistently shown performance improvements in exercises limited by acidosis.
Evidence from in vitro studies suggest that carnosine is also able to scavenge reactive oxygen species and prevent damage to the lipid components of cell membranes (Decker et al., 2000; 2001). However, literature is controversial and in vivo whole body relevance of HCDs as antioxidants remains in question. Due to its multiple effects (e.g., anti-oxidant, anti-glycation and aldehyde detoxification), carnosine has been considered an anti-ageing molecule (Hipkiss, 2009) capable of counteracting senescence in mice models (Yuneva et al., 2009). Despite the promising potential applications of carnosine to support human health (Sale et al., 2013), this topic remains poorly understood.
Other potentially relevant functions of carnosine and HCDs include the regulation of calcium sensitivity of the contractile apparatus as well as the regulation of calcium-handling in striated muscle. Studies indicate that increased carnosine can improve skeletal muscle contractile function, likely via calcium handing, although human studies do not confirm such observations.
In this project, multiple experimental approaches, including cell cultures, animal and human studies, could be used to stress all the putative biological and physiological roles of HCDs in relevant tissues. Specific studies will be designed to answer these fundamental questions in specific tissues.
Funding Notes
Full-time PhD registration is for 3 to 4 years.
Home/EU tuition fees: £4,121 (likely to rise in each subsequent year)
International tuition fees: £12,600 (likely to rise in each subsequent year)
Bench fee (annual): up to £8,000; negotiable depending upon the specific project.
If a student has not submitted his/her thesis by the end of year 3, he/she is required to enrol for a fourth year and pay the Completion Year Fee to enable him/her to complete and submit the thesis. The Completion Year Fee is £590 for 2016/17 (increases every year). No Bench fee is payable in year 4.
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